TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas

Z. Liu, K. Yanagisawa, S. Griesing, M. Iwai, K. Kano, N. Hotta, T. Kajino, Motoshi Suzuki, T. Takahashi

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

TTF-1, also known as NKX2-1, is a transcription factor that has indispensable roles in both lung development and physiology. We and others have reported that TTF-1 frequently exhibits high expression with increased copy number in lung adenocarcinomas, and also has a role as a lineage-survival oncogene through transcriptional activation of crucial target genes including ROR1 and LMO3. In the present study, we employed a global proteomic search for proteins that interact with TTF-1 in order to provide a more comprehensive picture of this still enigmatic lineage-survival oncogene. Our results unexpectedly revealed a function independent of its transcriptional activity, as TTF-1 was found to interact with DDB1 and block its binding to CHK1, which in turn attenuated ubiquitylation and subsequent degradation of CHK1. Furthermore, TTF-1 overexpression conferred resistance to cellular conditions under DNA replication stress (RS) and prevented an increase in consequential DNA double-strand breaks, as reflected by attenuated induction of pCHK2 and γH2AX. Our findings suggest that the novel non-transcriptional function of TTF-1 identified in this study may contribute to lung adenocarcinoma development by conferring tolerance to DNA RS, which is known to be inherently elicited by activation of various oncogenes.

Original languageEnglish
Pages (from-to)3740-3748
Number of pages9
JournalOncogene
Volume36
Issue number26
DOIs
Publication statusPublished - 29-06-2017
Externally publishedYes

Fingerprint

Oncogenes
DNA Replication
Double-Stranded DNA Breaks
Ubiquitination
Proteomics
Transcriptional Activation
Transcription Factors
Lung
Genes
Adenocarcinoma of lung
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Liu, Z., Yanagisawa, K., Griesing, S., Iwai, M., Kano, K., Hotta, N., ... Takahashi, T. (2017). TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas. Oncogene, 36(26), 3740-3748. https://doi.org/10.1038/onc.2016.524
Liu, Z. ; Yanagisawa, K. ; Griesing, S. ; Iwai, M. ; Kano, K. ; Hotta, N. ; Kajino, T. ; Suzuki, Motoshi ; Takahashi, T. / TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas. In: Oncogene. 2017 ; Vol. 36, No. 26. pp. 3740-3748.
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Liu, Z, Yanagisawa, K, Griesing, S, Iwai, M, Kano, K, Hotta, N, Kajino, T, Suzuki, M & Takahashi, T 2017, 'TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas', Oncogene, vol. 36, no. 26, pp. 3740-3748. https://doi.org/10.1038/onc.2016.524

TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas. / Liu, Z.; Yanagisawa, K.; Griesing, S.; Iwai, M.; Kano, K.; Hotta, N.; Kajino, T.; Suzuki, Motoshi; Takahashi, T.

In: Oncogene, Vol. 36, No. 26, 29.06.2017, p. 3740-3748.

Research output: Contribution to journalArticle

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AU - Suzuki, Motoshi

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Liu Z, Yanagisawa K, Griesing S, Iwai M, Kano K, Hotta N et al. TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas. Oncogene. 2017 Jun 29;36(26):3740-3748. https://doi.org/10.1038/onc.2016.524